Steroid antibiotic conjugates

ABSTRACT

The present invention describes steroid antibiotic conjugates. These single drug entities are formed connecting a steroid moiety and two same antibiotics moieties, or a steroid moiety and two different antibiotics moieties. Upon topical application to the eye, the conjugate hybrid would undergo enzymatic and/or hydrolytic cleavage to release the individual drugs.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/775,216 filed Mar. 8, 2013, the disclosure ofwhich is hereby incorporated in its entirety by reference.

FIELD OF THE INVENTION

The present invention describes steroid antibiotic conjugates. Thesesingle drug entities are formed connecting a steroid moiety and two sameantibiotics moieties, or a steroid moiety and two different antibioticsmoieties. Upon topical application to the eye, the conjugate hybridwould undergo enzymatic and/or hydrolytic cleavage to release theindividual drugs.

SUMMARY OF THE INVENTION

The antibiotic moieties and the steroid moiety, of the compoundsdisclosed herein are connected via two covalent bonds to a linker suchthat said compound degrades in vivo to yield the respective antibioticand the respective steroids. Each bond is an amide bond or an ester bonddepending on the nature of the compound. In other words, the single drugentity has one amide bond connecting to the antibiotic and/or one esterbond connecting to the other antibiotic and/or one ester bond connectingto the steroid.

Degradation of the ester or amide bonds generally, but not necessarily,yields the corresponding acid and alcohol or amine by hydrolysis or arelated reaction. A compound which degrades in vivo to yield theantibiotic and steroid, produces the active drugs belonging to distinctclasses at some point in the metabolic process of the claimed compound.In many cases, cleavage of the first amide or ester bond will releaseone active, and cleavage of the second amide or ester bond will releasethe second active and then the third active will be released if it isthe case.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention relates to a hybrid compoundcomprising a steroid moiety and two same antibiotics moieties, or apharmaceutical salt thereof, which are connected via two covalent bondsto a linker such that said compound degrades in vivo to yield therespective two antibiotics independently and the respective steroiddrug, wherein each bond is an amide bond or an ester bond.

In another aspect, the present invention relates to a compoundcomprising a steroid moiety and two different antibiotics moieties, or apharmaceutical salt thereof, which are connected via two covalent bondsto a linker such that said compound degrades in vivo to yield therespective two antibiotics independently and the respective steroiddrug, wherein each bond is an amide bond or an ester bond.

In another aspect, the present invention relates to a hybrid compoundcomprising a steroid moiety and two antibiotics moieties, which areconnected via separate covalent bonds to at least one linker each suchthat said covalent bond degrade in vivo to yield the respective twoantibiotics independently and the respective steroid drug.

In another aspect, the present invention relates to a hybrid compoundwherein the two antibiotics moieties are identical.

In another aspect, the present invention relates to a hybrid compoundwherein the two antibiotics moieties are different.

In another aspect, the present invention relates to a hybrid compoundwherein a first antibiotic moiety is directly linked to the steroidmoiety and further linked to the other antibiotic moiety via a linker.

In another aspect, the present invention relates to a hybrid compound afirst antibiotic moiety is linked to the steroid moiety via a linker andfurther linked to the other antibiotic moiety via another linker.

In another aspect, the present invention relates to a hybrid compoundwherein a first antibiotic moiety is linked to the steroid moiety via alinker and further linked to the other antibiotic moiety via anotherlinker.

In another aspect, the present invention relates to a hybrid compoundwherein the two antibiotic drug moieties are selected from the groupconsisting of: gatifloxacin, moxifloxacin, chloramphenicol, tobramycinand amikacin.

In another aspect, the present invention relates to a hybrid compoundwherein the steroid drug moiety is selected from the group consistingof: dexmethasone, betamethasone, triamcinolone acetonide, prednisoloneand hydrocortisone.

In another aspect, the present invention relates to a hybrid compoundwherein said linker comprises an ester, a carboxylate, a carbonyl, acarbonate, an amido, a carbamate, a ketone, an amino, an oxo, anethylene glycol, a polyethylene glycol moiety or an ethylene moiety.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a hybridcompound, comprising two antibiotic moieties and one steroid drugmoiety, which are connected via separate covalent bonds such that saidcovalent bonds degrade in vivo to yield the antibiotics and steroiddrugs, and wherein said pharmaceutical composition is formulated fortopical ophthalmic administration.

In another aspect, the present invention relates to a method comprisingadministrating to an eye of a mammal a pharmaceutical compositioncomprising a therapeutically effective amount of a hybrid compoundcomprising two antibiotic moieties and one steroid moiety, which areconnected via separate covalent bonds such that said covalent bondsdegrade in vivo to yield the antibiotics and the steroid drugs, andwherein said method is effective in the treatment of an inflammatorycondition or bacterial infection affecting said eye.

In another aspect, the present invention relates to a method whereinsaid hybrid compound has topical antibiotic and anti-inflammatoryactivity upon a surface of an eye, and wherein the hybrid compounddegrades on said surface into said active antibiotics and said steroiddrug, which are capable of penetrating beyond tissue of said surface

In another aspect, the present invention relates to a hybrid compoundcomprising at least one linker having at least two bonds, wherein saidbonds are asymmetrically degraded in vivo to release the antibiotic andsteroid drugs.

The hybrid compounds of the invention have both antibacterial andanti-inflammatory activities and are very useful compounds capable ofproducing the effect of an antibacterial drug and anti-inflammatory drugin monotherapy.

In another aspect, the present invention relates to a compound which isan active drug, which degrades in vivo into active antibacterial(s) andanti-inflammatory drug(s).

The hybrid drugs of the invention provide a unique delivery of anantibiotic and a steroid for the treatment of ophthalmic bacterialinfections and inflammation. A single drug entity is advantageous forindividual dosing of each drug because of the ability for simultaneousdosing and elimination of washout concerns when applying each drugseparately.

The use of an antibiotic/anti-inflammatory hybrid drug is indicatedwhere the risk of infection is high or where there is an expectationthat potentially dangerous numbers of bacteria will be present in theeye. The anti-inflammatory component of the composition is useful intreating inflammation associated with physical trauma to ophthalmictissues, inflammation associated with bacterial infections andinflammation resulting from surgical procedures. The combination of anantibiotic and anti-inflammatory is also useful in post-operativeinflammation where there is an increased chance of bacterial infection.The composition of the invention may also be used prophylactically inconnection with various ophthalmic surgical procedures that create arisk of bacterial infection. Other examples of ophthalmic conditionswhich may be treated with the compositions of the present inventioninclude infective conditions associated with inflammation and where theuse of anti-inflammatory is acceptable. Such conditions may include, butare not limited to conjunctivitis, keratitis, blepharitis,endophthalmitis, dacyrocystitis, hordeolum, corneal ulcers, red eye,hyperemia, anterior blepharitis, posterior blepharitis, meibomian glanddysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain,ocular pain and inflammation post-ocular surgery, bacterialconjunctivitis, anterior uveitis, post-surgical inflammation,inflammatory conditions of the palpebral and bulbar conjunctiva, cornea,and anterior segment of the globe, such as allergic conjunctivitis,ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction,superficial punctate keratitis, herpes zoster keratitis, iritis,cyclitis, selected infective conjunctivitis, corneal injury fromchemical radiation, or thermal burns, penetration of foreign bodies,allergy, and combinations thereof.

The hybrid drugs disclosed herein comprise antibiotics moietiesbelonging to distinct classes: fluoroquinolones, cephalosporins,chloramphenicol, aminoglycosides, penicillins, erythromycin, macrolideantibiotics and oxazolidionones.

Fluoroquinolones include, but are not limited to: levofloxacin,moxifloxacin, gatifloxacin, gemifloxacin, trovafloxacin, ofloxacin,ciprofloxacin, sparfloxacin, grepafloxacin, norfoxacin, enoxacin,lomefloxacin, fleroxacin, tosufloxacin, prulifloxacin, pazufloxacin,clinafloxacin, garenoxacin, and sitafloxacin.

Cephalosporins include, but are not limited to: loracarbef, cephalexin,cefuroxime, ceftriaxone, ceftaxime, ceftizoxime, ceftibuten,ceftazidime, cefprozil, cefpodoxime, cefoxitin, cefotetan, cefotaxime,cefoperazone, cefixime, cefepime, cefditoren, cefdinir, cefoperaxone,moxalactam, cefazolin, cefamandole, cefadroxil, cefaclor, cephalothin,cephradine, cephacetrile, and cephalothin.

Aminoglycosides include, but are not limited to: tobramycin,streptomycin, gentamicin, kanamycin, amikacin and netilmicin.

Penicillins include, but are not limited to: penicillin G, ticarcillin,methicillin, phenthicillin, cloxacillin, dicloxacillin, nafcillin,oxacillin.

Macrolide antibiotics include, but are not limited to: erythromycin andazithromycin.

Oxazolidinones include, but are not limited to: linezolid.

Further, the compounds disclosed herein comprise a steroidal drugselected from: dexmethasone, betamethasone, triamcinolone acetonide,prednisolone and hydrocortisone.

In another embodiment the compounds disclosed herein comprise at leastone antibiotic drug selected from levofloxacin, moxifloxacin,gatifloxacin, gemifloxacin, trovafloxacin, ofloxacin, ciprofloxacin,sparfloxacin, grepafloxacin, norfoxacin, enoxacin, lomefloxacin,fleroxacin, tosufloxacin, prulifloxacin, pazufloxacin, clinafloxacin,garenoxacin, sitafloxacin, loracarbef, cephalexin, cefuroxime,ceftriaxone, ceftaxime, ceftizoxime, ceftibuten, ceftazidime, cefprozil,cefpodoxime, cefoxitin, cefotetan, cefotaxime, cefoperazone, cefixime,cefepime, cefditoren, cefdinir, cefoperaxone, moxalactam, cefazolin,cefamandole, cefadroxil, cefaclor, cephalothin, cephradine,cephacetrile, cephalothin, chloramphenicol, tobramycin, streptomycin,gentamicin, kanamycin, amikacin, netilmicin, penicillin g, ticarcillin,methicillin, phenthicillin, cloxacillin, dicloxacillin, nafcillin andoxacillin.

In another embodiment the compounds disclosed herein comprise at leastone steroidal drug selected from: dexmethasone, betamethasone,triamcinolone acetonide, prednisolone and hydrocortisone.

Depending on the linking site, the hybrid compounds of the invention canbe represented by Schemes 1, wherein the antibiotic moieties can be thesame or different:

In another aspect the invention provides compounds which may comprise alinker moiety selected from, but not limited to, an ester, acarboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone,an amino, an oxo, an ethylene glycol, a polyethylene glycol, anethylene.

In another aspect, the invention provides compounds which may comprise alinker moiety comprising any combination of an ester, a carboxylate, acarbonyl, a carbonate, an amido, a carbamate, a ketone, an ethylene, anamino, an oxo, an ethylene glycol and/or a polyethylene glycol. Suchlinker moieties are exemplified below and linker structures areexemplified in Table 1.

Examples of ester moieties comprised in the linkers are:

Examples of carboxylate moieties comprised in the linkers are:

Example of a carbonyl moiety comprised in the linkers is

Example of a carbonate moiety comprised in the linkers is:

Examples of amido moieties comprised in the linkers are:

Example of carbamate moiety comprised in the linkers is:

Example of a ketone moiety comprised in the linkers is:

Examples of amino moieties comprised in the linkers are:

Example of an oxo moiety comprised in the linker is:

Example of ethylene glycol moieties comprised in the linkers are:

Example of polyethylene glycol moiety comprised in the linkers is:

Further the compounds disclosed herein comprise a linker selected fromTable 1:

TABLE 1 Linker Number Linker Structure n = 0 n = 1 n = 2 n = 3

L2 L1

L3

L4

L35 L5

L6

L7

L14

L15

L16

L46

L8

L9

L10

L18

L11

L19

L12

L13

L20

L21

L22

L23

L24

L25

L26

L27

L28

L29

L30

L31

L32

L33

L34

L35

L36

L37

L38

L39

L40

L41

L42

L43

L44

L45

L47

L48

L49

L50

L51

L52

L53

L54

L58

L56

L57

L59

L60

L61

L62

L63

L64

L65

L66

L67

L68 L103 L104

L69

L70

L71

L72

L73

L74

L75

L76

L77

L78

L79

L80

L81

L82

L83

L84

L85 L86

L87

L88

L89

L90

L91

L92

L93

L94

L95

L96

L97

L98

L99

L100 L101 L102

Further the compounds disclosed herein comprise at least one pro-drugmoiety selected from Table 2:

TABLE 2 Prodrug Structure Prodrug Number

P1

P2

P3

P4

P5

P6

P7

P8

P9

P10

P11

P12

P13

P14

P15

Compounds of the invention are shown in Table 3.

TABLE 3 Compound number IUPAC NAME 102-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 112-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-1-cyclopropyl-7-(4-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 12[({4-[1-cyclopropyl-3-({2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}carbonyl)oxy]methyl rel-7-[(3S)-3-aminoazepan-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 132-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-1-cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 142-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-1-cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 15rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 16rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 17rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-3-({2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxo1-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 18rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[4-({[(4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3- carboxylic acid 19rel-1-cyclopropyl-7[1-({[({1-cyclopropyl-7[4-({[(4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 20rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[1-({[(4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)-2-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid21 ({[4-(1-cyclopropyl-3-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-yl}carbonyl} oxy)methyl2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 22({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl]carbony}oxy)methyl 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]- 2-oxoethylrel-butanedioate 23({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methyl 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 242-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9S,10R,11R,13R,16S,17S)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylre1-7,7′-{(2-oxo-1,3-dioxole-4,5-diyl)bis[methanediyl(3-methylpiperazine-4,1-diyl)]}bis(1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate) 252-[(8R,9S,10R,11R,13R,14R,16R,17S)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-1-cyclopropyl-6-fluoro-7-{4-[({[2-(2-fluorobiphenyl-4-yl)propanoyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 262-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-1-cyclopropyl-6-fluoro-7-{4-[({[2-(2-fluorobiphenyl-4-yl)propanoyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 271,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl 2-[(8R,9S,10R,11R,13R,14R,16S,17S)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-benzene-1,4-dicarboxylate 281,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]- 2-oxoethylrel-butanedioate 29 1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]- 2-oxoethylrel-butanedioate 301,3-bis{[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 311,3-bis({[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}oxy)propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 321,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]oxy} propan-2-yl2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2- oxoethylrel-butanedioate 331,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]oxy}propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 342-({2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)propane-1,3-diyl relbis(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylate)

In another embodiment the compounds disclosed herein comprise onesteroid moiety and two antibiotic moieties.

In another embodiment the compounds disclosed herein comprise onesteroid moiety and two antibiotic moieties and at least one linkerselected from Table 1.

In another embodiment the compounds disclosed herein comprise onesteroid moiety and two antibiotic moieties and at least one linkerselected from Table 1 and one pro-drug moiety selected from Table 2.

In another embodiment the compounds disclosed herein comprise onesteroid moiety and two antibiotic moieties and two linkers selected fromTable 1 and two pro-drug moieties selected from Table 2.

In another embodiment the compounds disclosed herein comprise steroidmoiety and two antibiotic moieties and least two linkers selected fromTable 1 and one pro-drug moiety selected from Table 2.

In another embodiment the compounds disclosed herein comprise steroidmoiety and two antibiotic moieties and one linker selected from Table 1and two pro-drug moieties selected from Table 2.

In another embodiment the compounds disclosed herein comprise oneprednisolone moiety and two moxifloxacin moieties, such as:

-   2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;-   ({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methyl    2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-butanedioate.

In another embodiment the compounds disclosed herein comprise oneprednisolone moiety and one moxifloxacin moiety and one gatifloxacinmoiety such as:

-   2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-1-cyclopropyl-7-(4-{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;-   2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-1-cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;-   rel-1-cyclopropyl-7-[1-({[({1-cyclopropyl-7-[4-({[(4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[1-({[(4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)-2-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   ({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methyl    2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-butanedioate.

In another embodiment the compounds disclosed herein comprise oneprednisolone moiety and two gatifloxacin moieties such as:

-   ({[4-(1-cyclopropyl-3-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-yl]carbonyl}oxy)methyl    2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-butanedioate;-   rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[4-({[(4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-3-({2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-1-cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;-   1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl    2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-butanedioate;-   1,3-bis{[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}propan-2-yl    2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-butanedioate.

In another embodiment the compounds disclosed herein comprise onehydrocortisone moiety and one besifloxacin moiety and one gatifloxacinmoiety such as:

-   [({4-[1-cyclopropyl-3-({2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}carbonyl)oxy]methyl    rel-7-[(3S)-3-aminoazepan-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate.

In another embodiment the compounds disclosed herein comprise onedexamethasone and two gatifloxacin moieties such as:

-   rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl    2-[(8R,9S,10R,11R,13R,14R,16S,17S)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-benzene-1,4-dicarboxylate.

In another embodiment the compounds disclosed herein comprise onebethasone and two gatifloxacin moieties such as:

-   rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid.

In another embodiment the compounds disclosed herein comprise onehydrocortisone and two gatifloxacin moieties such as:

-   1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl    2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-butanedioate;-   1,3-bis({[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}oxy)propan-2-yl    2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-butanedioate;-   1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]oxy}propan-2-yl    2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-butanedioate.

In another embodiment the compounds disclosed herein comprise onehydrocortisone and two moxifloxacin moieties such as:

-   1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]oxy}propan-2-yl    2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl    rel-butanedioate;-   2-({2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)propane-1,3-diyl    relbis(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylate).

In another embodiment the invention provides a hybrid compoundcomprising two antibiotic moieties and a steroid drug moiety, or apharmaceutical salt thereof, which are connected via three separatecovalent bonds to a linker such that said covalent bonds degrade in vivoto yield independently the antibiotics and steroid drugs.

In another embodiment the invention provides a hybrid compoundcomprising two different antibiotic moieties and a steroid drug moiety,or a pharmaceutical salt thereof, which are connected via three separatecovalent bonds to a linker such that said covalent bonds degrade in vivoto yield independently the antibiotics and steroid drugs.

In another embodiment the invention provides a hybrid compoundcomprising two identical antibiotic moieties and a steroid drug moiety,or a pharmaceutical salt thereof, which are connected via three separatecovalent bonds to a linker such that said covalent bonds degrade in vivoto yield independently the antibiotics and steroid drugs.

In another embodiment the invention provides a hybrid compoundcomprising two different antibiotic moieties and a steroid drug moiety,or a pharmaceutical salt thereof, wherein the steroid is directly linkedto one antibiotic which is connected via a linker to the otherantibiotic and wherein the bonds degrade in vivo to yield independentlythe antibiotics and steroid drugs.

In another embodiment the invention provides a hybrid compoundcomprising two identical antibiotic moieties and a steroid drug moiety,or a pharmaceutical salt thereof, which are connected via four separatecovalent bonds to two different linkers such that said covalent bondsdegrade in vivo to yield independently the antibiotics and steroiddrugs.

In another embodiment the invention provides a hybrid compoundcomprising two identical antibiotic moieties and a steroid drug moiety,or a pharmaceutical salt thereof, which are connected via four separatecovalent bonds to two identical linkers such that said covalent bondsdegrade in vivo to yield independently the antibiotics and steroiddrugs.

In another embodiment the invention provides a pharmaceuticalcomposition comprising a hybrid compound comprising two antibioticmoieties and a steroid moiety, which are connected via three separatecovalent bonds to a linker such that said covalent bonds degrade in vivoto yield the antibiotics and the steroid drugs, wherein each bond is anester bond or an amide depending on the nature of the linker, whereinsaid pharmaceutical composition is formulated for topical ophthalmicadministration.

In another embodiment the invention provides a pharmaceuticalcomposition comprising a hybrid compound comprising two antibioticmoieties and a steroid moiety, which are connected via four separatecovalent bonds to two linkers such that said covalent bonds degrade invivo to yield the antibiotics and the steroid drugs, wherein each bondis an ester bond or an amide depending on the nature of the linker,wherein said pharmaceutical composition is formulated for topicalophthalmic administration.

In another embodiment the invention provides a pharmaceuticalcomposition comprising a hybrid compound comprising two identicalantibiotic moieties and a steroid moiety, which are connected via threeseparate covalent bonds to a linker such that said covalent bondsdegrade in vivo to yield the antibiotics and the steroid drugs, whereineach bond is an ester bond or an amide depending on the nature of thelinker, wherein said pharmaceutical composition is formulated fortopical ophthalmic administration.

In another embodiment the invention provides a pharmaceuticalcomposition comprising a hybrid compound comprising two differentantibiotic moieties and a steroid moiety, which are connected via threeseparate covalent bonds to a linker such that said covalent bondsdegrade in vivo to yield the antibiotics and the steroid drugs, whereineach bond is an ester bond or an amide depending on the nature of thelinker, wherein said pharmaceutical composition is formulated fortopical ophthalmic administration.

In another embodiment the invention provides a pharmaceuticalcomposition comprising a hybrid compound comprising two antibioticmoieties and a steroid moiety, which are connected via four separatecovalent bonds to two linkers such that said covalent bonds degrade invivo to yield the antibiotics and the steroid drugs, wherein each bondis an ester bond or an amide depending on the nature of the linker,wherein said pharmaceutical composition is formulated for topicalophthalmic administration.

In another embodiment the invention provides a pharmaceuticalcomposition comprising a hybrid compound comprising two identicalantibiotic moieties and a steroid moiety, which are connected via fourseparate covalent bonds to two linkers such that said covalent bondsdegrade in vivo to yield the antibiotics and the steroid drugs, whereineach bond is an ester bond or an amide depending on the nature of thelinker, wherein said pharmaceutical composition is formulated fortopical ophthalmic administration.

In another embodiment the invention provides a pharmaceuticalcomposition comprising a hybrid compound comprising two differentantibiotic moieties and a steroid moiety, which are connected via fourseparate covalent bonds to two linkers such that said covalent bondsdegrade in vivo to yield the antibiotics and the steroid drugs, whereineach bond is an ester bond or an amide depending on the nature of thelinker, wherein said pharmaceutical composition is formulated fortopical ophthalmic administration.

In another embodiment the invention provides a pharmaceuticalcomposition comprising a hybrid compound comprising two differentantibiotic moieties and a steroid moiety, which are connected via threeseparate covalent bonds to one linker such that said covalent bondsdegrade in vivo to yield the antibiotics and the steroid drugs, whereineach bond is an ester bond or an amide depending on the nature of thelinker, wherein said pharmaceutical composition is formulated fortopical ophthalmic administration.

In another embodiment the invention provides a hybrid compoundcomprising two linkers having four bonds, wherein said bonds areasymmetrically degraded in vivo to release the three active drugs.

Some compounds of the invention have at least one stereogenic center intheir structure. This stereogenic center may be present in an R or Sconfiguration, said R and S notation is used in correspondence with therules described in Pure Appli. Chem. (1976), 45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of the invention are able to form.

The acid addition salt form of a compound of the invention that occursin its free form as a base can be obtained by treating the free basewith an appropriate acid such as an inorganic acid, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid and the like; or an organic acid such as for example,acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaricacid, maleic acid, oxalic acid, tartaric acid, succinic acid, malicacid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric,methylsulfonic, ethanesulfonic, benzenesulfonic, formic acid and thelike (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G.Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).

The base addition salt form of a compound of the invention that occursin its acid form can be obtained by treating the acid with anappropriate base such as an inorganic base, for example, sodiumhydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide,ammonia and the like; or an organic base such as for example,L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like.(Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G.Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).

Compounds of the invention and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

In still another embodiment of the invention, there are provided methodsfor treating or preventing eye conditions such as: conjunctivitis,keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulcers,anterior blepharitis, posterior blepharitis, meibomian glanddysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain,ocular pain and inflammation post-ocular surgery, bacterialconjunctivitis, anterior uveitis, in a patient suffering thereof. Suchmethods can be performed, for example, by administering to a subject inneed thereof a therapeutically effective amount of at least one compoundof the invention, or any combination thereof, or pharmaceuticallyacceptable salts, hydrates, solvates, crystal forms thereof.

The present invention concerns the use of a compound of the invention ora pharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of conjunctivitis, keratitis, blepharitis,endophthalmitis, red eye, hyperemia, dacyrocystitis, hordeolum, cornealulcers, anterior blepharitis, posterior blepharitis, meibomian glanddysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain,ocular pain and inflammation post-ocular surgery, bacterialconjunctivitis, anterior uveitis.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

The compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

The compounds of the invention may also be administered aspharmaceutical compositions in a form suitable for topical use, forexample, as oily suspensions, as solutions or suspensions in aqueousliquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquidemulsions.

Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable salt thereof, asan active ingredient with conventional ophthalmically acceptablepharmaceutical excipients and by preparation of unit dosage suitable fortopical ocular use. The therapeutically efficient amount typically isbetween about 0.001 and about 5% (w/v), preferably about 0.001 to about2.0% (w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 4.5 and 8.0with an appropriate buffer system, a neutral pH being preferred but notessential. The formulations may also contain conventionalpharmaceutically acceptable preservatives, stabilizers and surfactants.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate.

A preferred surfactant is, for example, Tween 80. Likewise, variouspreferred vehicles may be used in the ophthalmic preparations of thepresent invention. These vehicles include, but are not limited to,polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers,carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin andpurified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar manner an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace of or in conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001 to about 5preservative   0-0.10 vehicle   0-40 tonicity adjustor   0-10 buffer0.01-10 pH adjustor q.s. pH 4.5-7.8 antioxidant as needed surfactant asneeded purified water to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution. One package may contain oneor more unit doses. Especially preservative-free solutions are oftenformulated in non-resealable containers containing up to about ten,preferably up to about five units doses, where a typical unit dose isfrom one to about 8 drops, preferably one to about 3 drops. The volumeof one drop usually is about 20-35 μl.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions such as conjunctivitis,keratitis, blepharitis, endophthalmitis, red eye, hyperemia,dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis,posterior blepharitis, meibomian gland dysfunction, dry eye disease(keratocojunctivitis sicca) ocular pain, ocular pain and inflammationpost-ocular surgery, bacterial conjunctivitis, anterior uveitis,post-surgical inflammation, inflammatory conditions of the palpebral andbulbar conjunctiva, cornea, and anterior segment of the globe, such asallergic conjunctivitis, ocular rosacea, dry eye, blepharitis, meibomiangland dysfunction, superficial punctate keratitis, herpes zosterkeratitis, iritis, cyclitis, selected infective conjunctivitis, cornealinjury from chemical radiation, or thermal burns, penetration of foreignbodies, allergy, and combinations thereof.

Thus, in further embodiments of the invention, there are providedmethods for treating conjunctivitis, keratitis, blepharitis,dacyrocystitis, endophthalmitis, red eye, hyperemia, hordeolum, cornealulcers, anterior blepharitis, posterior blepharitis, meibomian glanddysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain,ocular pain and inflammation post-ocular surgery, bacterialconjunctivitis, anterior uveitis, post-surgical inflammation,inflammatory conditions of the palpebral and bulbar conjunctiva, cornea,and anterior segment of the globe, such as allergic conjunctivitis,ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction,superficial punctate keratitis, herpes zoster keratitis, iritis,cyclitis, selected infective conjunctivitis, corneal injury fromchemical radiation, or thermal burns, penetration of foreign bodies,allergy, and combinations thereof.

Such methods can be performed, for example, by administering to asubject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one invention compound. Asused herein, the term “therapeutically effective amount” means theamount of the pharmaceutical composition that will elicit the biologicalor medical response of a subject in need thereof that is being sought bythe researcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

The present invention concerns also processes for preparing thecompounds of the invention. The compounds according to the invention canbe prepared analogously to conventional methods as understood by theperson skilled in the art of synthetic organic chemistry. Schemes A, B,C, D and E set forth below, illustrate how the compounds according tothe invention can be made.

It should be noted that the brief description on each of the arrows foreach conversion has been added for illustration purpose sonly and shouldnot be regarded as limiting with respect to the sequence of eachindividual step.

The following abbreviations are used in the examples:

-   CH₂Cl₂ dichloromethane-   EtOH ethanol-   Na₂SO₄ sodium sulfate-   DMF N,N dimethylformamide-   EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-   THF tetrahydrofuran-   BOO tert-butyl carbamate-   BOC₂O di-tert-butyl pyrocarbonate-   NaOH sodium hydroxide-   HCl hydrochlorique acid-   DMAP 4-Dimethylaminopyridine-   NaHCO₃ sodium bicarbonate-   CHCl₃ chloroform-   Na₂CO₃ sodium carbonate-   (n-Bu)₄NHSO₄ tetrabutylammonium hydrogen sulfate

In Scheme A BOO protected gatifloxacin reacted with prednisolone to forma directly coupled steroid antibiotic hybrid compound, which was coupleto a linker further coupled with a molecule of moxifloxacin. Scheme A isrepresentative of a Scheme 1C hybrid compound.

In Scheme B BOO a gatifloxacin molecule was coupled with linker andfurther coupled with a prednisolone molecule, which was further coupledwith a molecule of moxifloxacin via a linker. Scheme B is representativeof a Scheme 1D hybrid compound.

Scheme C shows the formation of a hybrid compound according to Scheme 1G.

Scheme D shows the formation of a hybrid compound according to Scheme 1Gwith a pro-drug moiety.

Scheme E shows the formation of a hybrid compound according to Scheme 1E.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereisomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereisomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of hydrogen ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACDLabs version 12.5 or ChemBioDrawUltra version 12.0.2.

In general, characterization of the compounds is performed according tothe following methods. Proton nuclear magnetic resonance (¹H NMR) andcarbon nuclear magnetic resonance (¹³C NMR) spectra were recorded on aVarian 300 or 600 MHz spectrometer in deuterated solvent. Chemicalshifts were reported as δ (delta) values in parts per million (ppm)relative to tetramethylsilane (TMS) as an internal standard (0.00 ppm)and multiplicities were reported as s, singlet; d, doublet; t, triplet;q, quartet; m, multiplet; br, broad. Data were reported in the followingformat: chemical shift (multiplicity, coupling constant(s) J in hertz(Hz), integrated intensity). The mass spectrometry data were determinedon a Shimadzu LCMS-IT-TOF instrument.

The formation of the hybrid compounds was checked by ¹H-NMR, comparingthe chemical shifts of the protons from the CH₂ group identified in theschemes shown below, and identified as “CH₂ ^(c)” for the startingmaterial and as “CH₂ ^(c*)” or “c*” for of the corresponding protons onthe newly formed hybrid molecule wherein “*” indicates the hybridcompound. Applicants have marked with arrows the location of theseprotons and the reaction site of the pro-drug moiety, where available.Each scheme shows the formation of the new hybrid drug. Each tabledescribes the results for the new hybrid drug and the linker number,where existing. The linker and pro-drug moiety numbers are as describedin Table 1 and 2 respectively.

It is to be understood that the embodiments of the invention disclosedherein are illustrative of the principles of the present invention.Other modifications that may be employed are within the scope of theinvention. Thus, by way of example, but not of limitation, alternativeconfigurations of the present invention may be utilized in accordancewith the teachings herein. Accordingly, the present invention is notlimited to that precisely as shown and described.

Examples of Compounds

Prednisolone reacted with two molecules of Moxifloxacin to form thefollowing hybrid compounds as shown in Scheme 1 with the resultsdescribed in Table 4; and as shown in Scheme 2 with the resultsdescribed in Table 5.

TABLE 4 * Comp. No. Linker Structure CH_(2c)* Mass 10 L46

5.12 (dd) 1201 (MH⁺)

TABLE 5 * Comp. No. Linker1 Linker2 Structure CH₂ ^(c)* Mass 23 L₁47L₂46

4.88 (in DMSO)

Prednisolone reacted with one molecule of Gatifloxacin and one moleculeof Moxifloxacin to form the following hybrid compounds as shown inScheme 3 with the results described in Table 6; and as shown in Scheme 4with the results described in Table 7; and as shown in Scheme 5 with theresults described in Table 8; and as shown in Scheme 6 with the resultsdescribed in Table 9; and as shown in Scheme 7 with the resultsdescribed in Table 10.

TABLE 6 * Comp. No. Linker1 Linker2 Structure CH₂ ^(c)* Mass 19 L₁52L₂46

4.98 (dd) 1371 (MNa⁺)

TABLE 7 * Comp. No. Linker 1 Linker2 Structure CH₂ ^(c)* Mass 20 L₁52L₂46

5.00 1371 (MNa⁺)

TABLE 8 * Comp. No. Linker 1 Linker2 Structure CH₂ ^(c)* Mass 22 L₁52L₂46

4.88 (in DMSO)

TABLE 9 * Comp. No. Linker Structure CH₂ ^(c)* Mass 11 L46

5.16 (dd) 1176 (MH⁺)

TABLE 10 * Comp. No. Linker Prodrug Structure CH₂ ^(c)* Mass 14 L46 P3

5.07 1309 (MH⁺)

Prednisolone reacted with two molecules Gatifloxacin to form thefollowing hybrid compounds as shown in Scheme 8 with the resultsdescribed in Table 11 and as shown in Scheme 9 with the resultsdescribed in Table 12 and as shown in Scheme 10 with the resultsdescribed in Table 13 and as shown in Scheme 11 with the resultsdescribed in Table 14 and as shown in Scheme 12 with the resultsdescribed in Table 15 and as shown in Scheme 13 with the resultsdescribed in Table 16.

TABLE 11 * Comp. No. Linker 1 Linker2 Structure CH₂ ^(c)* Mass 21 L₁56L₂7

4.98 (dd) 1301 (MNa⁺)

TABLE 12 * Comp. No. Linker 1 Linker2 Structure CH₂ ^(c)* Mass 18 L₁52L₂9

5.01 (dd) 134 (MNa⁺)

TABLE 13 * Comp. No. Linker Structure CH₂ ^(c)* Mass 17 L12

5.10 (dd) 1225 (MH⁺)

TABLE 14 * Comp. No. Linker Prodrug Structure CH₂ ^(c)* Mass 13 L46 P3

5.08 1283 (MH⁺)

TABLE 15 * Comp. No. Linker Structure CH₂ ^(c)* Mass 28 L50

5.02- 4.73   (m) 1249 (MH⁺)

TABLE 16 * Comp. No. Linker Prodrug Structure CH₂ ^(c)* Mass 30 L50 P3

5.26-4.81 (m) 1495 (MH⁺)

Hydrocortisone reacted with Gatifloxacin and with Besifloxacin to formthe following hybrid compounds as shown in Scheme 14 with the resultsdescribed in Table 17.

TABLE 17 * Comp. No. Linker Structure CH₂ ^(c)* Mass 12 L46

5.13 (dd) 1167 (MH⁺)

Dexmethasone reacted with two molecules of Gatifloxacin to form thefollowing hybrid compounds as shown in Scheme 15 with the resultsdescribed in Table 18 and as shown in Scheme 16 with the resultsdescribed in Table 19.

TABLE 18 * Comp. No. Linker Structure CH₂ ^(c)* Mass 15 L12

5.07 (dd) 1257 (MNa⁺)

TABLE 19 * Comp. No. Linker Structure CH₂ ^(c)* Mass 27 L51

5.22 (dd) 1329 (MH⁺)

Betamethasone reacted with two molecules of Gatifloxacin to form thefollowing hybrid compounds as shown in Scheme 17 with the resultsdescribed in Table 20.

TABLE 20 * Comp. No. Linker Structure CH₂ ^(c*) Mass 16 L12

5.00 (dd) 1257 (MNa⁺)

Hydrocortisone reacted with two molecules of Gatifloxacin to form thefollowing hybrid compounds as shown in Scheme 18 with the resultsdescribed in Table 21 and as shown in Scheme 19 with the resultsdescribed in Table 22.

TABLE 21 * Comp. No. Linker Structure CH₂ ^(c*) Mass 31 L48

5.03 (dd) 1398 (MH⁺) 29 L50

5.06- 4.77 (m) 1273 (MH⁺)

TABLE 22 * Comp. No. Linker Prodrug Structure CH₂ ^(c*) Mass 32 L48 P3

5.01 (dd) 1642.8 (MH⁺)

Hydrocortisone reacted with two molecules of Moxifloxacin to form thefollowing hybrid compounds as shown in Scheme 20 with the resultsdescribed in Table 23.

TABLE 23 * Comp. No. Linker Prodrug Structure CH₂ ^(c*) Mass 34 L49 P3

5.10 (dd) 1401 (MH⁺) 33 L48 P3

4.98 (dd) 1695 (MH⁺)

In vitro Metabolic Stability in Human Recombinant Carboxylesterases

Human recombinant carboxylesterases were purchased from a commercialvendor (BD Gentest™, Bedford, Massachusettes). All metabolic stabilityexperiments were performed in triplicate in 96-well plate format. Thefinal incubation mixture contained 1 μM test compound, 0.3 mg/mL cornealprotein homogenate or 0.1 mg/mL human recombinant carboxylesterasemixture in a final volume of 0.5 mL 0.1 M potassium phosphate buffer(pH=6.0). The final percentage of solvent in the incubation was lessthan 1.0% to prevent inhibition of enzymatic activity. Following apre-incubation at 37° C., test article was added to initiate thereaction. At designated time points (typically less than 60 minutes tocapture the linear range of metabolite formation), 0.05 mL aliquots wereremoved from the incubation mixtures using a clean pipet tip andimmediately placed in organic solvent to stop any esterase activity. Thehydrolysis to the metabolites was confirmed to be due to esteraseactivity and not chemical lability.

The samples were analyzed by liquid chromatography with massspectrometry (LC-MS/MS) detection to determine the metaboliteconcentrations resulting from the metabolism of the hybrid compounds.Internal standards were used to compensate for variability from sampleprocessing, chromatographic elution, mass spectrometer response and ionsuppression by matrix components.

Results

Table 24 lists the rate of metabolite formation in human recombinantcarboxylesterases.

TABLE 24 Rate of Rate of Rate of formation formation formation *Comp.Metabolite 1 Metabolite 2 Metabolite 3 No. (nM/min/mg) (nM/min/mg)(nM/min/mg) 28 13.9 ± 1.1 55.9 ± 4.4 N/A Gatifloxacin Prednisolone 1013.8 ± 1.5 14.6 ± 1.1 N/A Moxifloxacin Prednisolone 11  256 ± 29 35.4 ±5.0 69.7 ± 14.2 Prednisolone Gatifloxacin Moxifloxacin 12  155 ± 31 54.9± 8.1 91.0 ± 22.2 Prednisolone Gatifloxacin Besifloxacin 30 41.8 ± 10.26.16 ± 1.36 N/A Prednisolone Gatifloxacin 18 81.2 ± 9.0  107 ± 9 N/APrednisolone Gatifloxacin N/A = Not applicable

The data demonstrate that linkage of a fluoroquinolone (e.g.gatifloxacin, moxifloxacin, and besifloxacin) and a steroid (e.g.prednisolone) as a single hybrid compound was hydrolyzed enzymaticallyin human recombinant carboxylesterases to their respective individualantibiotic and steroid drugs.

What is claimed is:
 1. A hybrid compound comprising a steroid and twoantibiotic moieties, or a pharmaceutical salt thereof, which areconnected via separate covalent bonds to at least one linker each suchthat said covalent bond degrade in vivo to yield the respective twoantibiotics independently and the respective steroid drug.
 2. The hybridcompound according to claim 1, wherein the two antibiotics moieties areidentical.
 3. The hybrid compound according to claim 1, wherein the twoantibiotics moieties are different.
 4. The hybrid compound according toclaim 1, wherein a first antibiotic moiety is directly linked to thesteroid moiety and further linked to the other antibiotic moiety via alinker.
 5. The hybrid compound according to claim 1, wherein a firstantibiotic moiety is linked to the steroid moiety via a linker andfurther linked to the other antibiotic moiety via another linker.
 6. Thehybrid compound according to claim 1 wherein the two antibiotic drugmoieties are selected from the group consisting of: gatifloxacin,moxifloxacin, chloramphenicol, tobramycin and amikacin.
 7. The hybridcompound according to claim 1 wherein the steroid drug moiety isselected from the group consisting of: dexmethasone, betamethasone,triamcinolone acetonide, prednisolone and hydrocortisone.
 8. The hybridcompound according to claim 1 wherein said linker comprises an ester, acarboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone,an amino, an oxo, an ethylene glycol, a polyethylene glycol moiety or anethylene moiety.
 9. A pharmaceutical composition comprising atherapeutically effective amount of a hybrid compound, comprising twoantibiotic moieties and one steroid drug moiety, which are connected viaseparate covalent bonds wherein said covalent bonds degrade in vivo toyield the antibiotics and steroid drugs, and wherein said pharmaceuticalcomposition is formulated for topical ophthalmic administration.
 10. Amethod comprising administrating to an eye of a mammal a pharmaceuticalcomposition comprising a therapeutically effective amount of a hybridcompound comprising two antibiotic moieties and one steroid moiety,which are connected via separate covalent bonds wherein said covalentbonds degrade in vivo to yield the antibiotics and the steroid drugs,and wherein said method is effective in the treatment of an inflammatorycondition or bacterial infection affecting said eye.
 11. The methodaccording to claim 10 wherein said hybrid compound has topicalantibiotic and anti-inflammatory activity upon a surface of an eye, andwherein the hybrid compound degrades on said surface into said activeantibiotics and said steroid drug, which are capable of penetratingbeyond tissue of said surface eye.
 12. The hybrid compound according toclaim 1 comprising at least one linker having at least two bonds,wherein said bonds are asymmetrically degraded in vivo to release theantibiotic and steroid drugs.
 13. The hybrid compound according to claim1, selected from:2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-1-cyclopropyl-7-(4-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;[({4-[1-cyclopropyl-3-({2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}carbonyl)oxy]methylrel-7-[(3S)-3-aminoazepan-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-1-cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-1-cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl}oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid;rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid;rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-3-({2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid;rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[4-({[(4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid;rel-1-cyclopropyl-7-[1-({[({1-cyclopropyl-7-[4-({[(4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid;rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[1-({[(4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)-2-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid;({[4-(1-cyclopropyl-3-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-yl]carbonyl}oxy)methyl2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-butanedioate;({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methyl2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-butanedioate;({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methyl2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-butanedioate;2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl2-[(9S,10R,11R,13R,16S,17S)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-7,7′-{(2-oxo-1,3-dioxole-4,5-diyl)bis[methanediyl(3-methylpiperazine-4,1-diyl)]}bis(1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate);2-[(8R,9S,10R,11R,13R,14R,16R,17S)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-1-cyclopropyl-6-fluoro-7-{4-[({[2-(2-fluorobiphenyl-4-yl)propanoyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-1-cyclopropyl-6-fluoro-7-{4-[({[2-(2-fluorobiphenyl-4-yl)propanoyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl2-[(8R,9S,10R,11R,13R,14R,16S,17S)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-benzene-1,4-dicarboxylate;1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-butanedioate;1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-butanedioate;1,3-bis{[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}propan-2-yl2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-butanedioate;1,3-bis({[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}oxy)propan-2-yl2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-butanedioate;1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl]-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]oxy}propan-2-yl2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-butanedioate;1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]oxy}propan-2-yl2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethylrel-butanedioate; and2-({2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)propane-1,3-diylrelbis(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylate).